Closely related pancreatic polypeptides have recently been isolated from several species, including humans, and found to have hormonal properties. Pancreatic polypeptide (PP) is localized within discreet endocrine pancreatic islet cells and stored in their secretory granules. These and other data suggest a physiological role for PP. Evidence is accumulating that PP has a role in nutrient homeostasis and that it may be involved in the pathogenesis or sequelae of several types of diabetes mellitus. The relationships of PP with other islet hormones are not clear and such investigations are needed to better understand the diabetic syndrome and nutrient homeostasis in general. The present unavailability of pure PP largely accounts for the lack of research into this area. The first object of our research would be to apply our newly developed techniques of solid phase synthesis, purification and analysis of large polypeptides to the rapid preparation of large quantities of pure PP. Our recent syntheses of demonstrably pure beta-endorphin and related analogs (31 amino acid residues) and of vasoactive intestinal polypeptide (29 residues) in high yields, indicate promising results with PP and PP analogs (36 residues). We would develop in vitro and in vivo bioassays in rats and modify our existing assays to screen the biological activities of our synthetic PP and subsequent analogs. Initially, we would look for dose-related effects on somatostatin, insulin and glucagon release, hepatic glycogenolysis, intestinal nutrient absorption and accumulation of cAMP in liver and gut. Our early studies showed that PP suppresses hepatic portal and systemic plasma somatostatin in vivo, and we will focus on extending this assay. Structure-activity work, highly feasible by our synthetic approach, would follow and could lead to analogs with therapeutic value in treating diabetes mellitus and other disorders.